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CardioVascular and Interventional Radiology

, Volume 42, Issue 2, pp 239–249 | Cite as

Radioablation by Image-Guided (HDR) Brachytherapy and Transarterial Chemoembolization in Hepatocellular Carcinoma: A Randomized Phase II Trial

  • Konrad MohnikeEmail author
  • Ingo G. Steffen
  • Max Seidensticker
  • Peter Hass
  • Robert Damm
  • Nils Peters
  • Ricarda Seidensticker
  • Kerstin Schütte
  • Jörg Arend
  • Jan Bornschein
  • Tina Streitparth
  • Christian Wybranski
  • Gero Wieners
  • Patrick Stübs
  • Peter Malfertheiner
  • Maciej Pech
  • Jens Ricke
Clinical Investigation Interventional Oncology
  • 117 Downloads
Part of the following topical collections:
  1. Interventional Oncology

Abstract

Background and Aims

The aim of this single-center, open-label phase II study was to assess the efficacy of image-guided high-dose-rate (HDR) brachytherapy (iBT) compared with conventional transarterial embolization (cTACE) in unresectable hepatocellular carcinoma.

Methods

Seventy-seven patients were treated after randomization to iBT or cTACE, as single or repeated interventions. Crossover was allowed if clinically indicated. The primary endpoint was time to untreatable progression (TTUP). Eligibility criteria included a Child–Pugh score of ≤ 8 points, absence of portal vein thrombosis (PVT) at the affected liver lobe, and ≤ 4 lesions. Survival was analyzed by using the Cox proportional hazard model with stratification for Barcelona Clinic Liver Cancer (BCLC) stages.

Results

Twenty patients were classified as BCLC-A (iBT/cTACE 8/12), 35 as BCLC-B (16/19), and 22 as BCLC-C (13/9). The 1-, 2-, and 3-year TTUP probabilities for iBT compared with cTACE were 67.5% versus 55.2%, 56.0% versus 27.4%, and 29.5% versus 11.0%, respectively, with an adjusted hazard ratio (HR) of 0.49 (95% confidence interval 0.27–0.89; p = 0.019). The 1-, 2-, and 3-year TTPs for iBT versus cTACE were 56.0% versus 28.2%, 23.9% versus 6.3%, and 15.9% versus 6.3%, respectively, with an adjusted HR of 0.49 (0.29–0.85; p = 0.011). The 1-, 2-, and 3-year OS rates were 78.4% versus 67.7%, 62.0% versus 47.3%, and 36.7% versus 27.0%, respectively, with an adjusted HR of 0.62 (0.33–1.16; p = 0.136).

Conclusions

This explorative phase II trial showed a superior outcome of iBT compared with cTACE in hepatocellular carcinoma and supports proceeding to a phase III trial.

Keywords

Ablation Liver cancer BCLC HCC RCT 

Abbreviations

AASL

American Association for the Study of the Liver

BCLC

Barcelona Clinic Liver Cancer (staging system)

CI

Confidence interval

CLIP

Cancer of the Liver Italian Program

CT

Computed tomography

cTACE

Conventional transarterial chemoembolization

CTCAE

Common Terminology Criteria for Adverse Events

DEB-TACE

Drug-eluting beads transarterial chemoembolization

EASL

European Association for the Study of the Liver

HCC

Hepatocellular carcinoma

HDR

High dose rate

HR

Hazard ratio

iBT

Interstitial brachytherapy

OS

Overall survival

PVT

Portal vein thrombosis

RFA

Radiofrequency ablation

SBRT

Stereotactic body radiotherapy

TTP

Time to progression

TTUP

Time to untreatable progression

Notes

Funding

This study was funded exclusively by the University of Magdeburg.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Consent for Publication

Consent for publication was obtained for every individual person’s data included in the study.

Financial Support

This work was funded exclusively by the University of Magdeburg.

Ethical Considerations

The study was conducted in accordance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, and ICH-GCP. The study protocol and all study-related documentation were approved by all relevant authorities (Ethics Committee of the Medical Faculty, University of Magdeburg, 44/06).

References

  1. 1.
    Jaeck D, Bachellier P, Oussoultzoglou E, Weber JC, Wolf P. Surgical resection of hepatocellular carcinoma. Post-operative outcome and long-term results in Europe: an overview. Liver Transpl. 2004;10:S58–63.CrossRefGoogle Scholar
  2. 2.
    Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–14.CrossRefGoogle Scholar
  3. 3.
    Cheng BQ, Jia CQ, Liu CT, et al. Chemoembolization combined with radiofrequency ablation for patients with hepatocellular carcinoma larger than 3 cm: a randomized controlled trial. JAMA. 2008;299:1669–77.CrossRefGoogle Scholar
  4. 4.
    Helmberger T, Dogan S, Straub G, et al. Liver resection or combined chemoembolization and radiofrequency ablation improve survival in patients with hepatocellular carcinoma. Digestion. 2007;75:104–12.CrossRefGoogle Scholar
  5. 5.
    Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37:429–42.CrossRefGoogle Scholar
  6. 6.
    Vogl TJ, Naguib NN, Nour-Eldin NE, et al. Review on transarterial chemoembolization in hepatocellular carcinoma: palliative, combined, neoadjuvant, bridging, and symptomatic indications. Eur J Radiol. 2009;72:505–16.CrossRefGoogle Scholar
  7. 7.
    Cucchetti A, Piscaglia F, Cescon M, Ercolani G, Pinna AD. Systematic review of surgical resection vs radiofrequency ablation for hepatocellular carcinoma. World J Gastroenterol. 2013;19:4106–18.CrossRefGoogle Scholar
  8. 8.
    Cucchetti A, Piscaglia F, Cescon M, et al. An explorative data-analysis to support the choice between hepatic resection and radiofrequency ablation in the treatment of hepatocellular carcinoma. Dig Liver Dis. 2014;46:257–63.CrossRefGoogle Scholar
  9. 9.
    Takayasu K, Arii S, Ikai I, et al. Overall survival after transarterial lipiodol infusion chemotherapy with or without embolization for unresectable hepatocellular carcinoma: propensity score analysis. AJR Am J Roentgenol. 2010;194:830–7.CrossRefGoogle Scholar
  10. 10.
    Collettini F, Schnapauff D, Poellinger A, et al. Hepatocellular carcinoma: computed-tomography-guided high-dose-rate brachytherapy (CT-HDRBT) ablation of large (5–7 cm) and very large (> 7 cm) tumours. Eur Radiol. 2012;22:1101–9.CrossRefGoogle Scholar
  11. 11.
    Mohnike K, Wieners G, Schwartz F, et al. Computed tomography-guided high-dose-rate brachytherapy in hepatocellular carcinoma: safety, efficacy, and effect on survival. Int J Radiat Oncol Biol Phys. 2010;78:172–9.CrossRefGoogle Scholar
  12. 12.
    Ricke J, Mohnike K, Pech M, et al. Local response and impact on survival after local ablation of liver metastases from colorectal carcinoma by computed tomography-guided high-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys. 2010;78:479–85.CrossRefGoogle Scholar
  13. 13.
    Ricke J, Thormann M, Ludewig M, et al. MR-guided liver tumor ablation employing open high-field 1.0T MRI for image-guided brachytherapy. Eur Radiol. 2010;20:1985–93.CrossRefGoogle Scholar
  14. 14.
    Ricke J, Wust P, Stohlmann A, et al. CT-guided interstitial brachytherapy of liver malignancies alone or in combination with thermal ablation: phase I–II results of a novel technique. Int J Radiat Oncol Biol Phys. 2004;58:1496–505.CrossRefGoogle Scholar
  15. 15.
    Ricke J, Wust P, Wieners G, et al. Liver malignancies: CT-guided interstitial brachytherapy in patients with unfavorable lesions for thermal ablation. J Vasc Interv Radiol. 2004;15:1279–86.CrossRefGoogle Scholar
  16. 16.
    Tselis N, Chatzikonstantinou G, Kolotas C, Milickovic N, Baltas D, Zamboglou N. Computed tomography-guided interstitial high dose rate brachytherapy for centrally located liver tumours: a single institution study. Eur Radiol. 2013;23:2264–70.CrossRefGoogle Scholar
  17. 17.
    Mohnike K, Neumann K, Hass P, et al. Radioablation of adrenal gland malignomas with interstitial high-dose-rate brachytherapy: efficacy and outcome. Strahlenther Onkol. 2017;193:612–9.CrossRefGoogle Scholar
  18. 18.
    Mohnike K, Wolf S, Damm R, et al. Radioablation of liver malignancies with interstitial high-dose-rate brachytherapy: complications and risk factors. Strahlenther Onkol. 2016;192:288–96.CrossRefGoogle Scholar
  19. 19.
    Hata M, Tokuuye K, Sugahara S, et al. Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus. Cancer. 2005;104:794–801.CrossRefGoogle Scholar
  20. 20.
    Lee SU, Park JW, Kim TH, et al. Effectiveness and safety of proton beam therapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis. Strahlenther Onkol. 2014;190:806–14.CrossRefGoogle Scholar
  21. 21.
    Sugahara S, Nakayama H, Fukuda K, et al. Proton-beam therapy for hepatocellular carcinoma associated with portal vein tumor thrombosis. Strahlenther Onkol. 2009;185:782–8.CrossRefGoogle Scholar
  22. 22.
    Mohnike K, Sauerland H, Seidensticker M, et al. Haemorrhagic complications and symptomatic venous thromboembolism in interventional tumour ablations: the impact of peri-interventional thrombosis prophylaxis. Cardiovasc Intervent Radiol. 2016;39:1716–21.CrossRefGoogle Scholar
  23. 23.
    Cannistra SA. Phase II trials in journal of clinical oncology. J Clin Oncol. 2009;27:3073–6.CrossRefGoogle Scholar
  24. 24.
    Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the study of the liver. J Hepatol. 2001;35:421–30.CrossRefGoogle Scholar
  25. 25.
    Bruix J, Sherman M. Practice Guidelines Committee AAftSoLD. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36.CrossRefGoogle Scholar
  26. 26.
    Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359:1734–9.CrossRefGoogle Scholar
  27. 27.
    Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35:1164–71.CrossRefGoogle Scholar
  28. 28.
    Lencioni R. Chemoembolization in patients with hepatocellular carcinoma. Liver Cancer. 2012;1:41–50.CrossRefGoogle Scholar
  29. 29.
    Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33:41–52.CrossRefGoogle Scholar
  30. 30.
    Forner A, Gilabert M, Bruix J, Raoul JL. Treatment of intermediate-stage hepatocellular carcinoma. Nat Rev Clin Oncol. 2014;11:525–35.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2018

Authors and Affiliations

  • Konrad Mohnike
    • 1
    • 11
    • 12
    Email author
  • Ingo G. Steffen
    • 2
  • Max Seidensticker
    • 3
    • 12
  • Peter Hass
    • 4
  • Robert Damm
    • 1
  • Nils Peters
    • 11
  • Ricarda Seidensticker
    • 3
    • 12
  • Kerstin Schütte
    • 5
  • Jörg Arend
    • 6
  • Jan Bornschein
    • 7
  • Tina Streitparth
    • 3
  • Christian Wybranski
    • 8
  • Gero Wieners
    • 3
  • Patrick Stübs
    • 9
  • Peter Malfertheiner
    • 10
  • Maciej Pech
    • 1
    • 12
  • Jens Ricke
    • 3
    • 12
  1. 1.Department of Radiology and Nuclear MedicineUniversity of MagdeburgMagdeburgGermany
  2. 2.Department of RadiologyCharitéBerlinGermany
  3. 3.Department of RadiologyLuwig-Maximilians-University MunichMunichGermany
  4. 4.Department of RadiotherapyUniversity of MagdeburgMagdeburgGermany
  5. 5.Nils-Stensen-HospitalOsnabrueckGermany
  6. 6.Department of SurgeryUniversity of MagdeburgMagdeburgGermany
  7. 7.Translational Gastroenterology UnitOxford University HospitalsOxfordUK
  8. 8.Department of RadiologyUniversity Hospital of CologneCologneGermany
  9. 9.DRK-Hospital Berlin-KoepenickBerlinGermany
  10. 10.Department of Gastroenterology, Hepatology and InfectiologyUniversity of MagdeburgMagdeburgGermany
  11. 11.Diagnostisch Therapeutisches Zentrum am Frankfurter TorBerlinGermany
  12. 12.Deutsche Akademie für Mikrotherapie e.V.MagdeburgGermany

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